Among the antisickling agents recently described the imidoesters appear to possess several advantages that warrant further development for potential clinical use in patients with severe symptomatic sickle hemoglobinopathy. This proposal focuses on the monofunctional imidoester methyl acetimidate (MAI). MAI is effective in vitro at concentrations as low as 2.5 mM. It reacts rapidly and irreversibly with the hemoglobin in intact erythrocytes without producing significant detrimental effects upon the integrity of the cell, its enzymes, or its glycolytic or oxidative pathways. The oxygen affinity of the treated erythrocytes is significantly increased and crosslinked hemoglobin is produced. No acute toxicity was found in mice. Based on these observations further clinical development of this agent will be pursued. Toxicity studies will be carried out in two species. A centrifugal approach to extracorporeal erythrocyte treatment will be developed in animals. Success would lead to pilot studies in patients and ultimately and hopefully to an effective prophylaxis against the vasoocclusive episodes which shorten the life expectancy of most of the patients who suffer from these disorders.